The normal electrophysiologic behaviour of the heart is determined by ordered propagation of excitatory stimuli that result in rapid depolarization of the cardiac cell, followed by a slower repolarization. The sum of these events creates the cardiac action potential in individual myocytes. Cardiac rhythm disturbances can be caused by abnormalities of impulse generation, propagation or the duration and configuration of such individual cardiac action potentials. The action potentials are generated by the integrated activity of specific ion currents through various transmembrane spanning ion channels with specific selectivity for individual ions (e.g. potassium, sodium, calcium, see Grant A O. Circ. Arrhythmia Electrophysiol. 2009; 2:185-194). The majority of these ion channels have been cloned and thus, their molecular components are known. This knowledge has enabled a more effective search for selective ion channel blockers, as specific ion channel targets can be recombinantly over-expressed in mammalian cells and be used for high capacity screening.
Electrophysiological studies in the early 1950s showed the importance of the movement of K+ out of the cell to produce repolarization after the rapid depolarizing spike. Over the last 60 years, the introduction of single channel recording techniques and molecular cloning has resulted in a deeper understanding of cardiac repolarization and of the different potassium channels involved. Potassium channels are divided into:
a. Voltage gated channels (KV 1-9)
b. Calcium activated channels (KCa)
c. Inward rectifier channels (Kir 1-6)
d. Tandem pore domain channels (TWIK, TREK, TASK, TRAAK)
The pharmacology of cardiac potassium channels is disclosed in Tamargo et al., Cardiovascular Research (2004), 62, 9-33.
The expression of all these channels differs in various part of the cardiac muscle. Some channels are rather homogenously expressed, whereas some channels have a more chamber specific expression. Thus, the ultra rapid delayed rectifier (KV1.5) and the acetylcholine operated inward rectifier (Kir 3.1/Kir3.4) are shown to be rather atrial selective in their expression (Wang Z et al. Circ. Res. (1993); 73:1061-1076 and Schram G et al. Circ. Res. (2002); 90:939-50).
Compounds that block outwardly directed repolarizing potassium current will prolong the cardiac action potential duration (APD). An increase of APD prolongs the is corresponding effective refractory period (ERP), the time period during which the cell can not be re-exited to generate a new action potential (the so-called Class III antiarrhythmic action, see Singh B N et al. Br. J. Pharmacol. (1970); 39:675-689). As a group, such Class III compounds prevent cardiac tachyarrhythmia, such as atrial fibrillation (AF) based on so-called re-entrant mechanisms. In the normal myocardium, pacemaker cells of the sinoatrial node initiate the cardiac impulse. The cardiac impulse is then propagated to neighbouring excitable cells, and in this way depolarization spreads across the atria, through the atrioventricular node, and to the ventricles in a co-ordinated fashion. The impulse is unidirectional because of the refractoriness to depolarization of the preceding myocardial tissue. However, atrial re-entry circuits occur when the propagating impulse does not die out because it continues to encounter excitable atrial tissue, which it can depolarize. This occurs where there is an area of atrial refractory tissue encountered by the impulse that blocks its progress as a wave front. Following its circuit around this central area, the wave front may return to its point of origin after the ERP has finished and re-exited the atrial tissue, thereby forming a re-entrant circuit (Waldo A L. Lancet (1993); 341:1189-1193). Drugs that prolong the atrial ERP thus will minimize the risk for such re-excitation.
However, drugs that cause ERP prolongation by block of potassium current that exists in both atria and ventricle will prolong APD in both kind of myocardial tissue. Excessive APD prolongation in the ventricle or in the specialised conduction tissue, the so-called Purkinje Fibres, may increase the risk for a proarrhythmic event, i.e. the antiarrhythmic action is replaced by a situation in which arrhythmias may be created. A typical proarrhythmia caused by delay of ventricular repolarization is Torsades de pointes (TdP), which is a life threatening proarrhythmia, limiting the use of antiarrhythmic compounds of the Class III type. TdP is caused by so called early after depolarizations (EADs) defined as single or repetitive depolarizations originating from the AP plateau and which can propagate to and excite surrounding cardiac tissue. TdP is a life-threatening ventricular arrhythmia as it sometimes can transfer into ventricular fibrillation. Thus, the use of compounds which as antiarrhythmic mechanism delay cardiac repolarization in the ventricle, always carry a risk for such dangerous proarrhythmias and as a consequence, the development of several such compounds has been halted and some compounds which have is reached the market have been withdrawn (Redfern W S et al. Cardiovasc. Res. (2003); 58:32-45).
AF is the most common sustained cardiac arrhythmia and in 2008 10 million patients world-wide suffered from AF and this is estimated to grow to 13 million by 2020. The presence of AF is associated with a significant increase in the risk of adverse cardiovascular events and is an independent predictor of stroke and congestive heart failure (Estes N A et al. J. Am. Coll. Cardiol. (2008); 51:865-884; Fang M C et al. J. Am. Coll. Cardiol. (2008); 51:810-815). Moreover, patients quality of life is greatly reduced as a result of symptoms such as dizziness, palpitations, and reduced exercise capacity (Thrall G et al. Am. J. Med. (2006); 119:448e1-448e19).
The therapeutic goals in patients with AF are to reduce thromboembolic risk, to restore and maintain normal sinus rhythm and to control ventricular rate during AF. Thromboembolic risk is mostly reduced by anticoagulation therapy. Restoration and maintenance of sinus rhythm is obtained by using electrical or pharmacological cardioversion, or by ablation or surgery, followed by pharmacological control of sinus rhythm to prevent AF relapse. When AF is permanent and cardioversion is undoable, the arrhythmia has to be accepted and the main therapy is to control ventricular rate predominantly by drugs that delay AV nodal conduction, but also in some cases by AV nodal ablation and pacemaker implantation (Markides V et al. Heart 2003; 89:939-943).
Pharmacological therapy for atrial fibrillation is described in Expert Opin. Investig. Drugs (2009) 18 (4), 417-431. However, there is currently no optimal drug treatment for sinus rhythm maintenance available, and a novel compound with better efficacy for sinus rhythm maintenance and without limiting unacceptable ventricular side effects is urgently needed.
The parasympathetic nervous system acts through the vagus nerve to regulate the heart rate and the conduction properties of atrial, atrioventricular and ventricular tissue. In animal models, parasympathetic stimulation has been shown to predispose the atria to AF and attenuation of vagal effects has been shown to prevent AF induction (Chiou C W et al. Circulation (1997); 95:2573-2584). Parasympathetic effects to the heart are largely mediated through interaction with the acetylcholine operated inward rectifier channel (i.e. the KACh channel). The cardiac KACh channel is comprised of two homologous transmembrane spanning proteins—GIRK1 and GIRK 4 (Kir3.1 and Kir3.4) (Krapivinsky G et al. Nature (1995); 374:135-141), and both homomers are needed to build the functional channel. Increased activity of the KACh channel results in shortening of the atrial APD and ERP, thus favouring AF based on the re-entry mechanism. An interesting finding is that one of the pore forming homomers are prominently expressed in atrial muscle but are largely absent in ventricles (Dobyzynski H et al. J. Histochem. Cytochem. (2001); 49:1221-1234). This finding explain the fact that vagal stimulation in anaesthetized animals (dog, rabbit) causes substantial ERP shortening in the atria, whereas no such effects are noted in the ventricles, thus confirming the atrial selectivity of the KACh channel. Advantages of atrial selectivity in antiarrhythmic drug treatment of AF are discussed in Li et al., Cardiovascular & Hematological Agents in Medicinal Chemistry (2009), 7 (1), 64-75.
Another important finding is ionic remodelling induced by atrial pacing and induction of AF also results in increased constitutively active KACh channels by enhancing spontaneous channel openings, even in the absence of acetylcholine (Cha T J et al. Circulation (2006); 113:1730-1737). This finding also is shown in atrial muscle from AF patients (Dobra D et al. Circulation (2005); 112:3697-3706). Thus, block of IKACh will lead to atrial ERP prolongation in all AF patients, not only so in patients with AF of vagal origin. Ehrlich in J. Cardiovasc describes IKACh as a potential target for treatment of AF. Pharmacol. (2008), 52 (2), 129-135.